Positioning imatinib for pulmonary arterial hypertension: a dose finding phase 2 study
Author(s)
Type
Journal Article
Abstract
Rationale: Imatinib, 400 mg daily, reduces pulmonary vascular resistance and improves exercise capacity in patients with pulmonary arterial hypertension. Concerns about safety and tolerability limit its use.
Objectives: We sought to identify a safe and tolerated dose of oral imatinib between 100 mg and 400 mg daily and evaluate its efficacy.
Methods: Oral imatinib was added to the background therapy of 17 patients with pulmonary arterial hypertension, including 13 who were implanted with devices that provide daily measurements of cardiopulmonary hemodynamics and physical activity. The first patient was started on 100 mg daily. The next 12 patients, recruited serially, were started on 200 mg, 300 mg, or 400 mg daily, following a continuous reassessment dose-finding model. An extension cohort (Patients 14–17) received 100 mg or 200 mg daily.
Measurements and Main Results: The continuous reassessment model recommended starting dose was 200 mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (−6.5 mm Hg; 95% confidence interval [CI] = −2.4 to −10.6; P < 0.01) and total pulmonary resistance (−2.8 Wood units; 95% CI = −1.5 to −4.2; P < 0.001), with no significant change in cardiac output. The reduction in total pulmonary resistance was dose and exposure dependent; the reduction from baseline with imatinib, at 200 mg daily, was −20.3% (95% CI = −14.3 to −26.3%). Total pulmonary resistance and night heart rate declined steadily over the first 28 days of treatment and remained below baseline up to 40 days after imatinib withdrawal.
Conclusions: Oral imatinib, 200 mg daily, is well tolerated as an add-on treatment for pulmonary arterial hypertension. A delay in the return of cardiopulmonary hemodynamics to baseline was observed after imatinib was stopped.
Objectives: We sought to identify a safe and tolerated dose of oral imatinib between 100 mg and 400 mg daily and evaluate its efficacy.
Methods: Oral imatinib was added to the background therapy of 17 patients with pulmonary arterial hypertension, including 13 who were implanted with devices that provide daily measurements of cardiopulmonary hemodynamics and physical activity. The first patient was started on 100 mg daily. The next 12 patients, recruited serially, were started on 200 mg, 300 mg, or 400 mg daily, following a continuous reassessment dose-finding model. An extension cohort (Patients 14–17) received 100 mg or 200 mg daily.
Measurements and Main Results: The continuous reassessment model recommended starting dose was 200 mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (−6.5 mm Hg; 95% confidence interval [CI] = −2.4 to −10.6; P < 0.01) and total pulmonary resistance (−2.8 Wood units; 95% CI = −1.5 to −4.2; P < 0.001), with no significant change in cardiac output. The reduction in total pulmonary resistance was dose and exposure dependent; the reduction from baseline with imatinib, at 200 mg daily, was −20.3% (95% CI = −14.3 to −26.3%). Total pulmonary resistance and night heart rate declined steadily over the first 28 days of treatment and remained below baseline up to 40 days after imatinib withdrawal.
Conclusions: Oral imatinib, 200 mg daily, is well tolerated as an add-on treatment for pulmonary arterial hypertension. A delay in the return of cardiopulmonary hemodynamics to baseline was observed after imatinib was stopped.
Date Issued
2025-06-01
Date Acceptance
2025-03-13
Citation
American Journal of Respiratory and Critical Care Medicine, 2025, 211 (6), pp.1018-1027
ISSN
1073-449X
Publisher
American Thoracic Society
Start Page
1018
End Page
1027
Journal / Book Title
American Journal of Respiratory and Critical Care Medicine
Volume
211
Issue
6
Copyright Statement
Copyright © 2025 by the American Thoracic Society. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https:// creativecommons.org/licenses/by/4.0/). For reprints, please contact Diane Gern (dgern@thoracic.org).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40080796
Subjects
adaptive trial design
implanted haemodynamic sensors
remote monitoring
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2025-03-13